The lysosomal storage disorders (LSDs) are characterized by deficiencies in lysosomal enzymes resulting from mutations in genes that encode the enzyme proteins and related cofactors. Lysosomal enzymes degrade most biomolecules, the products of which are then recycled in a process that is essential for cell health and growth. LSDs result in accumulation of undegraded products in lysosomes and concomitant cell enlargement, dysfunction, and death. The clinical manifestations of LSDs include neuronal lipidosis, leukodystrophy, mucopolysaccharidosis, and storage histiocytosis.
Pompe disease (Glycogen storage disease type II; acid maltase deficiency; MIM 232300) is a myopathy, similar to limb-girdle muscular dystrophy in its late-onset form, which results from acid α-glucosidase (GAA) deficiency in striated and smooth muscle. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) has been effective in a subset of patients with Pompe disease. Infantile-onset Pompe disease affects the heart and skeletal muscle primarily, and causes death early in childhood from cardiorespiratory failure related to an underlying hypertrophic cardiomyopathy, if initiation of ERT is delayed or the patient fails to respond sustainably due to high, sustained anti-GAA antibodies. See Hirschhorn & Reuser, “Glycogen Storage Disease Type II: Acid Alpha-Glucosidase (acid maltase) Deficiency,” in Scriver et al. (Eds.), The Metabolic & Molecular Bases of Inherited Diseases, 2001, New York: McGraw-Hill, pp. 3389-3420; Kishnani et al., J. Pediatr., 2006, 149:89-97; Kishnani et al., Mol. Genet. Metab., 2010, 99:26-33.
GAA normally functions as an acid hydrolase that metabolizes lysosomal glycogen, and GAA deficiency causes lysosomal glycogen accumulation in virtually all tissues (Ponce et al., Am. J. Pathol., 1999, 154:1089-1096). The availability of ERT with rhGAA has prolonged survival and ameliorated the cardiomyopathy of infantile Pompe disease (Kishnani et al., Neurology, 2007, 68:99-109). In late-onset Pompe disease ERT has largely resulted in stabilization of the disease process from a pulmonary and motor perspective (Case et al., Mol. Genet. Metab., 2008, 95:233-235). Documented limitations of ERT in Pompe disease include the requirement for frequent intravenous infusions of high levels of GAA to achieve efficacy, degree of pre-ERT muscle damage, and the possibility of humoral immunity (Kishnani et al., Mol. Genet. Metab., 2010, 99:26-33; Amalfitano et al., Genet. Med., 2001, 3:132-138). The rhGAA doses are markedly higher than doses required for ERT in other lysosomal storage disorders, reflecting the high threshold for correction of GAA deficiency in the skeletal muscle of Pompe disease patients (Desnick, J. Inherit. Metab. Dis., 2004, 27:385-410).
Even in CRIM-positive infants with Pompe disease, a lack of complete efficacy from ERT has been observed. Children with Pompe disease have residual motor developmental delays and respiratory insufficiency (Nicolino et al., Genet. Med., 2009, 11:210-219). Hypernasal speech and swallowing difficulties indicated residual oromotor abnormalities despite long-term ERT in infantile-onset Pompe disease (Jones et al., Dysphagia, 2010, 25:277-283). Many young children with Pompe disease require temporary or long-term assisted ventilation (Nicolino et al., Genet. Med., 2009, 11:210-219). Strabismus and ptosis have been observed frequently among children with Pompe disease, while receiving ERT (Yanovitch et al., J. Pediatr. Ophthalmol. Strabismus, 2010, 47:34-40). Each of these abnormalities demonstrates a lack of complete efficacy from ERT. Patients with late-onset Pompe disease have severe pulmonary insufficiency may progress to respiratory failure while receiving ERT (Kobayashi et al., Mol. Genet. Metab., 2010, 100:14-19). Many individuals with late-onset Pompe disease have residual gait abnormalities despite adherence to ERT, indicating a relative lack of response of leg muscles (Strothotte et al., J. Neurol., 2010, 257:91-97).
Accordingly, there exists a continuing need for new therapies for lysosomal storage diseases, such as Pompe disease. The present invention provides therapeutic strategies premised upon increased expression of cell surface receptors that bind to lysosomal enzymes. This approach may be effective as a stand alone therapy or for enhancement of other therapies, such as ERT.